This project previously identified the membrane scavenger receptor CD36 as a facilitator of cellular uptake of long chain fatty acid (FA) and showed that its deletion in mice markedly reduces FA uptake by heart, skeletal muscle and adipose tissue. The deletion also reduces gut chylomicron secretion and delays clearance of postprandial lipids. This renewal submission is focused on CD36-dependent FA signaling. CD36 can transduce intracellular signals through its interaction with tyrosine kinases and our recent findings support importance of this signaling in determining the metabolic fate of the FA. FA-induced CD36 signaling triggers conversion of polyunsaturated FA into the bioactive eicosanoids, mediates neurotransmitter release for gustatory fat perception, directs absorbed FA to chylomicron formation and triggers release by enteroendocrine cells of cholecystokinin and secretin, peptides with important roles in fat absorption and satiety. Our preliminary data also show that in myocytes, FA uptake enhances FA oxidation via CD36 signaling to activate the LKB1-AMPK pathway. Importance of CD36 to human FA metabolism was demonstrated by several groups including ours and genetic variants in CD36 were shown to associate with risk of the metabolic syndrome. Our recent data on the relationships between tissue expression profiles of CD36 transcripts and insulin sensitivity of obese subjects strongly support a key role for adipocyte CD36, which was a significant predictor of insulin sensitivity systemically and in liver and muscle. In aim 1, we will determine the metabolic and disease significance of CD36-mediated FA signaling using in vitro cell systems and mice models. In aim 2, we propose based on our recent identification of the CD36 amino acid residue required for FA uptake and signaling to examine the structural properties of the FA binding pocket and the influence of FA binding on CD36 membrane configuration. The CD36-protein interactions important for signal transduction will also be examined. In aim 3, to gain insight into tissue specific regulation of CD36 level whic determines FA homeostasis across tissues we will explore the factors that regulate alternate promoter usage of the human CD36 gene and the stability of alternate transcripts. The studies proposed should provide information on the importance of FA signaling in the regulation of FA utilization and metabolic health. The insight generated into CD36 structure and the regulation of tissue CD36 expression could help design strategies to target the protein more specifically and in a tissue specific manner.